Peripheral decarboxylase inhibitors paradoxically induce aromatic L-amino acid decarboxylase
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ARTICLE OPEN
Peripheral decarboxylase inhibitors paradoxically induce
aromatic L-amino acid decarboxylase
Anouke van Rumund 1,2 ✉, Lukas Pavelka3,4, Rianne A. J. Esselink1,2, Ben P. M. Geurtz5, Ron A. Wevers 5
, Brit Mollenhauer6,7,
Rejko Krüger3,4,8, Bastiaan R. Bloem1,2 and Marcel M. Verbeek1,5
Peripheral decarboxylase inhibitors (PDIs) prevent conversion of levodopa to dopamine in the blood by the enzyme aromatic L-
amino acid decarboxylase (AADC). Alterations in enzyme activity may contribute to the required higher dosages of levodopa
observed in many patients with Parkinson’s disease. We evaluated the effect of levodopa/PDI use on serum AADC enzyme activity.
Serum AADC enzyme activity was evaluated in three independent cohorts of patients with Parkinson’s disease or parkinsonism
(n = 301) and compared between patients on levodopa/PDI vs. patients not on this medication. AADC enzyme activity was elevated
in 62% of patients on levodopa/PDI treatment, compared to 19% of patients not on levodopa/PDI (median 90 mU/L vs. 50 mU/L, p
< 0.001). Patients with elevated AADC activity had longer disease duration and higher doses of levodopa/PDI. These findings may
implicate that peripheral AADC induction could underlie a waning effect of levodopa, necessitating dose increases to maintain a
sustained therapeutic effect.
npj Parkinson’s Disease (2021)7:29 ; https://doi.org/10.1038/s41531-021-00172-z
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INTRODUCTION the effect of chronic levodopa/PDI use on serum AADC enzyme
Levodopa is the mainstay of pharmacotherapy for patients with activity.
Parkinson’s disease (PD). Levodopa is typically administered with a
peripheral decarboxylase inhibitor (PDI), benserazide or carbidopa.
PDIs bind irreversibly to pyridoxal-5-phospate (PLP), the active
form of vitamin B6. PLP is required for the functioning of RESULTS
numerous enzymes and proteins. One of its many functions is to Group differences
act as a coenzyme for activation of L-amino acid decarboxylase Serum AADC enzyme activity was evaluated in a discovery cohort
(AADC), which catalyzes the conversion of levodopa in dopamine. and validated in two independent cohorts of patients with PD or
PDIs thus prevent peripheral conversion of levodopa to dopa- parkinsonism (n = 301) and compared between patients on
mine1, thereby diminishing side effects such as nausea or levodopa/PDI (n = 140) vs. patients not on this medication (n =
orthostatic hypotension that are caused by high systemic 161). Baseline characteristics of the study population and main
dopamine levels. Moreover, PDIs prolong the half-life of levodopa results are shown in Table 1. There were 197 patients diagnosed
in blood, thereby increasing the amount of levodopa that crosses with PD and 104 patients with another neurodegenerative or
the blood–brain barrier and boosting its therapeutic efficacy. They movement disorder (atypical parkinsonism (n = 55), secondary
cannot cross the blood–brain barrier and therefore have no effect parkinsonism (n = 27), dementia (n = 10), tremor or dystonia (n =
on conversion of levodopa into dopamine in the brain. However, 7), and other (n = 5, e.g., restless legs syndrome, late onset ataxia).
in a substantial part of PD patients sooner or later response Median AADC enzyme activity was elevated in patients using
fluctuations occur, the therapeutic window narrows and larger levodopa/PDI (median 90 mU/L) compared to patients not using
doses of levodopa are necessary with a greater likelihood of side levodopa in all three cohorts (median 50 mU/L, p < 0.001). There
effects. These phenomena are correlated to disease duration and was no significant difference between patients with PD or other
severity, suggesting that increased loss of dopaminergic innerva- movement disorders with levodopa/PDI (median 96 vs. 82 mU/L, p
tion of the striatum is largely responsible2–6. However, recent work 0.29) and the same groups without levodopa/PDI (median 50 vs.
offered additional explanations, namely peripheral mechanisms 49 mU/L, p 0.94, Fig. 1). An elevated AADC level (>79 mU/L) was
altering the bioavailability and, accordingly, the efficacy of found in 62% of patients using levodopa/PDI, compared to 19% of
levodopa. For example, gut microbiota may modify levodopa’s patients without levodopa (p < 0.001). Patients with an elevated
bioavailability by expressing the enzyme tyrosine decarboxylase AADC were older, had a longer disease duration, and had a higher
that can convert levodopa into dopamine, thereby reducing the daily levodopa dose. Multiple logistic regression analysis showed
amount of levodopa available for the brain7. We here examine an increased likelihood of elevated AADC for patients using
another peripheral obstacle for levodopa to reach the brain, levodopa (OR 6.6, 95% CI 2.8–15.6, p 0.001, adjusted for age,
namely induced AADC activity in blood. Specifically, we evaluated gender, diagnosis, disease duration, and daily levodopa/PDI dose).
1
Department of Neurology, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands. 2Radboudumc Center of
Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands. 3Clinical and Experimental Neuroscience, Luxembourg Centre for Systems Biomedicine, University of
Luxembourg, Esch-sur-Alzette, Luxembourg. 4Parkinson’s Research Clinic, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg. 5Department of Laboratory Medicine,
Radboud University Medical Center, Nijmegen, The Netherlands. 6Center of Parkinsonism and Movement Disorders, Paracelsus-Elena-Klinik, Kassel, Germany. 7University Medical
Center, Department of Neurology, Göttingen, Germany. 8Transversal Translational Medicine, Luxembourg Institute of Health, Strassen, Luxembourg. ✉email: Anouke.
vanrumund@radboudumc.nl
Published in partnership with the Parkinson’s FoundationA.van Rumund et al.
2
Table 1. Baseline characteristics of Radboudumc, Kassel, and Luxembourg cohorts.
Radboudumc10 Kassel11 Luxembourg12 Three cohorts
discovery cohort validation cohort validation cohort
Levodopa/PDI use Yes No Yes No Yes No Yes No
Patients, n 27 108 60 31 50 25 137 164
Diagnosis 15/12 71/37 31/29 5/26 50/0 25/0 96/41 101/63
PD/other diagnosisa
Age (years), 64 ± 9 60 ± 10 72 ± 8 70 ± 12 81 ± 6 79 ± 6 74 ± 10 65 ± 12
mean ± SD
Gender, 14/13 71/37 39/21 15/16 26/24 13/12 79/58 99/65
men/women
Diagnosis (years), 2 0 4 3 4 1 3 0
median (IQR) (1–4) (0-1) (2–7) (2–6) (1–7) (0–3) (1–6) (0-2)
Hoehn and Yahr score, 2.5 2.5 4 1 2 2 2.5 2
median (IQR) (2–3) (1.5–3) (3–4) (0-2.5) (2–3) (2–3) (2–4) (1.5–3)
MDS-UPDRS III score, 41 ± 14 35 ± 17 34 ± 16 19 ± 14 35 ± 18 41 ± 16 36 ± 17 33 ± 17
mean ± SD
Levodopa daily dose, 300 – 450 – 30 – 388 –
median (IQR) (150–544) (250–600) (300–531) (250–550)
Serum AADC 114b 52b 85b 48b 90b 42b 90b 50b
(mU/L), median (IQR) (64–145) (39–75) (63–125) (37–64) (70–113) (25–59) (65–126) (36–68)
Elevated serum AADC 19b (70%) 22b (20%) 36b (60%) 4b (13%) 30b (60%) 5b (20%) 85b (62%) 31b (19%)
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(>79 mU/L), n (%)
AADC aromatic L-amino acid decarboxylase enzyme activity, IQR interquartile range, n/a not available, PD Parkinson’s disease, PDI peripheral decarboxylase
inhibitor, SD standard deviation, MDS-UPDRS III Movement Disorder Society Unified Parkinson’s Disease Rating Scale part III.
a
Other neurodegenerative or movement disorder (atypical parkinsonism (n = 55), secondary parkinsonism (n = 27), dementia (n = 10), tremor or dystonia
(n = 7), and other (n = 5, e.g., restless legs syndrome, late onset ataxia).
b
Differences between subgroups with vs. without levodopa/PDI use are significant (p < 0.001), analyzed using Mann–Whitney U test for comparison of two
groups.
Higher daily doses of levodopa/PDI increased the likelihood of hypotension, documented in 36%) and constipation (as possible
elevated AADC (Fig. 2). interfering factor for medication effect, documented in 35%).
Medication characteristics
DISCUSSION
There was no significant difference in AADC enzyme activity
We found that serum AADC enzyme activity is markedly elevated
between patients with and without sustained release levodopa
in patients using levodopa with a PDI compared to patients not
medication or between carbidopa vs. benserazide. Dose frequency using (levodopa with) a PDI. This AADC induction is paradoxical,
was not different between patients with normal vs. elevated since PDIs are administered in order to inhibit AADC activity,
AADC. Patients with elevated AADC used more often and higher thereby increasing levodopa’s therapeutic efficacy while reducing
daily doses of other dopaminergic medication (Table 2). Dopa- any systemic side effects. AADC induction, as a consequence of
mine agonists and COMT inhibitors were used more often by and response to chronic levodopa/PDI use, may therefore increase
patients with elevated AADC (dopamine agonists 36% vs. 18%, p the peaks and troughs in plasma levodopa levels contributing to
= 0.001; COMT inhibitors 12% vs. 4%, p = 0.004), but were unlikely the development of response fluctuations. This is important since
to interact with AADC enzyme activity directly (AADC activity in pulsatile stimulation of dopamine receptors is believed to play an
patients with vs. without this medication was similar). Use of other important role in the development of dyskinesias2. In the past
comedication (MAO-B inhibitors, amantadine, serotonergic med- decades, there has been a longstanding discussion as to why and
ication) was comparable. how levodopa loses effectiveness. It is remarkable, however, that
AADC, the enzyme that converts levodopa into dopamine, has
Dopaminergic response only received minimal consideration in this context.
Serum AADC induction by PDIs was noted only once before in a
Among the 96 PD patients using levodopa, a beneficial
small longitudinal study in 1989, but was not followed up ever
dopaminergic response (defined as (1) documented history of
since8. This earlier study showed that the inhibitory effect of
marked improvement of motor function after initiation of 25 mg carbidopa ended ~90 min after oral intake. Then, AADC
dopaminergic treatment and/or with dose increases or marked activity returned to baseline levels. This baseline serum AADC
worsening with dose decreases or (2) documented history of activity rose gradually after 3–4 weeks of levodopa/PDI use8,9.
marked on/off fluctuations, including predictable end-of-dose AADC induction could not be explained by levodopa-related
wearing off) was present in 71% of patients with normal AADC enzyme induction, since intake of levodopa without PDI did not
activity vs. 73% with elevated AADC activity (p = 0.17). Response induce AADC. Moreover, it was not explained by general liver
fluctuations were present in 18% of the PD patients with normal enzyme induction, since it was not observed in patients with
AADC activity vs. 23% with elevated AADC (dyskinesias 6% vs. 9%, chronic use of known liver enzyme inducers such as the
p = 0.71, and wearing off 13% vs. 19%, p = 0.55). These group antiepileptic drug phenytoin8. Instead, a specific induction of
differences were not significant. There were no differences in side the serum AADC enzyme concentration as a result of compensa-
effects (nausea, only documented in 17%, and orthostatic tory autoregulation may be considered as underlying cause for
npj Parkinson’s Disease (2021) 29 Published in partnership with the Parkinson’s FoundationA.van Rumund et al.
3
Fig. 2 Likelihood of increased serum AADC. The likelihood of
elevated serum AADC increases with daily levodopa/PDI dose. Odds
ratios and 95% CI for elevated serum AADC enzyme activity
(>79 mU/L) are shown per category of daily PDI dose (levodopa/
PDI formulations are 4:1), analyzed with multiple logistic regression
adjusted for age, gender, disease duration, and diagnosis. AADC
aromatic L-amino acid decarboxylase, CI confidence interval, PDI
Fig. 1 Serum AADC enzyme activity in non-neurological controls, peripheral decarboxylase inhibitor. ***significant at the p < 0.001 level.
patients with and without chronic use of levodopa/PDI. AADC
enzyme activity is elevated in patients on, compared to patients not
on, levodopa/PDI treatment. Median AADC activity is shown with
In this study, patients with high AADC activity used higher doses of
interquartile range. Dashed line: cutoff value of AADC 79 mU/L, levodopa and more frequently used dopamine agonists and COMT
based on the 95th percentile of 49 controls free from neurological inhibitors, perhaps to compensate for the relative loss of levodopa
disease. ***The difference is significant at the p < 0.001 level efficacy. In line with our findings, a recent study has demonstrated
(Mann–Whitney U). 1 data point is outside the axis limits: PD patient that gut microbiota may also convert levodopa into dopamine even
on LDOPA/PDI with AADC 663 mU/L. AADC aromatic L-amino acid before resorption7. Thus, peripheral conversion of levodopa into
decarboxylase, LDOPA levodopa, other Dx patients with other dopamine, both in the gut and in blood, might compromise
neurodegenerative or movement disorder than Parkinson’s disease,
PD Parkinson’s disease, PDI peripheral decarboxylase inhibitor.
bioavailability and diminish the therapeutic efficacy of levodopa over
time. There are preliminary indications that higher doses of PDI may
increase the treatment effect of levodopa14,15.
our observations. The precise pathophysiological mechanism for Our study was neither designed to study all possible underlying
serum AADC induction remains to be established. pharmacokinetic mechanisms of AADC induction nor the clinical
One possible underlying or contributing factor might be chronic consequences and therefore has its limitations. First, this is a
(partial) vitamin B6 depletion. Chronic treatment with levodopa retrospective study of three cohorts, none of which was designed
and PDIs is associated with (1) partial vitamin B6 depletion, since
specifically for this purpose. Therefore, duration of levodopa use
PDIs bind irreversibly to PLP, the active form of vitamin B6, and (2)
and time of blood collection in relation to last levodopa intake were
with a dysfunctional methionine metabolism, which is character-
neither routinely documented nor standardized. Second, AADC
ized by an increased methylmalonic acid, increased homocysteine,
activity was measured only once for each patient (cross-sectionally);
and deficiencies of vitamin B6, folate (vitamin B11), and vitamin
B1210,11. Exogenous pyridoxine (vitamin B6) enhances peripheral a longitudinal study could provide clearer perspectives onto the
levodopa degradation. Based on plasma levodopa levels and its dynamics of AADC activity. Third, this study lacked power to detect
metabolites, this enhancing effect of exogenous pyridoxine on significant differences in treatment complications in the subgroup
peripheral levodopa degradation seems extra strong in patients of PD patients with levodopa/PDI, therefore implications of our
with chronic levodopa use. This could be explained by chronic findings on the management of PD patients are yet unclear.
(partial) vitamin B6 depletion, AADC induction, or both12. Ideally, AADC activity should be evaluated in patients before
The paradoxical induction of AADC activity could hypothetically start with levodopa and at several time points during treatment,
necessitate a gradual increase in required levodopa dosage, due to with evaluation of diurnal fluctuations and cumulative intake of
increased conversion into dopamine in blood, and negatively affect levodopa medication. Further pharmacokinetic studies addressing
levodopa’s efficacy, inducing response fluctuations and causing side the complex of neurochemical responses and treatment
effects. PD patients in advanced disease stages may need up to responses after chronic levodopa use are needed to provide
tenfold higher daily levodopa doses than PD patients in early disease more insight in the clinical and therapeutic consequences of
stages. It is widely assumed that this is due to more comprehensive AADC induction. Future studies in this area should also measure
dopaminergic neuronal cell death, creating a larger dopamine deficit. levels of PLP and other vitamin B6 compounds, alongside with
However, since at disease onset already 50–80% of dopaminergic AADC activity. Moreover, studies on the clinical and biochemical
neurons in the substantia nigra have degenerated13, it is difficult to effect of higher doses of PDI may be warranted.
understand that a relatively small further increase in dopaminergic This study provides an impetus for further research and
cell death is solely responsible for this dramatic loss of drug efficacy. discussion regarding the biochemical adaptations occurring after
Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 29A.van Rumund et al.
4
Ethics statement
Table 2. Patient characteristics in subgroups with normal and
For all three cohorts, the study protocol was approved by the local medical
elevated (>79 mU/L) serum AADC enzyme activity.
ethics committees: “Commissie Mensgebonden Onderzoek regio Arnhem-
Normal AADC High AADC p value Nijmegen” in the Netherlands; the Ethics Committee of the University of
Goettingen in Germany; and the National Research Ethics Committee in
Serum AADC activity 14–79 79–663 Luxembourg. All participants provided written informed consent prior to
range, mU/L enrollment.
Patients, n 185 116
Diagnosis 114/71 83/33 NSb AADC enzyme activity measurements
PD/other diagnosisa Venous blood samples were obtained at the time of enrollment in the
c cohort study. Blood was processed at the study site via standardized
Age (years), 68 ± 12 71 ± 11 0.048
procedures into serum, including rapid transport to the adjacent lab,
mean ± SD
centrifugation of the tubes, aliquoting in small standardized volumes, and
Gender, 114/71 64/52 NSb storage in biobanks at −80 °C. Serum samples from Kassel and Luxemburg
men/women were sent on dry ice to the Radboud University Medical Center. Enzymatic
Symptoms (years), 2.5 3.3 0.006c conversion of levodopa into dopamine was determined as described
median (IQR) (1.5–5.0) (2.0–6.0) previously19. First, a mixture of 150 μL serum and 150 μL PLP (the active
form of vitamin B6 in order to activate the AADC enzyme, 0.7 mM, Merck
Diagnosis (years), 1.0 2.0A.van Rumund et al.
5
DATA AVAILABILITY and by a MJFF grant (ID: 1480). The study sponsors had no influence on the study
Anonymized data will be shared on request from any qualified investigator for design, collection, and analysis of data, the writing of the paper, or the decision to
purposes of replicating procedures and results. submit the paper. Additionally, we acknowledge the joint effort of the NCER-PD
consortium members generally contributing to the Luxembourg Parkinson’s Study as
listed below: Geeta Acharya, Gloria Aguayo, Myriam Alexandre, Dominic Allen, Wim
Received: 1 October 2020; Accepted: 19 February 2021; Ammerlann, Maike Aurich, Federico Baldini, Rudi Balling, Peter Banda, Katy
Beaumont, Regina Becker, Camille Bellora, Daniela Berg, Fay Betsou, Sylvia Binck,
Alexandre Bisdorff, Dheeraj Bobbili, Kathrin Brockmann, Jessica Calmes, Lorieza
Castillo, Nico Diederich, Rene Dondelinger, Daniela Esteves, Jean-Yves Ferrand, Ronan
Fleming, Manon Gantenbein, Thomas Gasser, Piotr Gawron, Lars Geffers, Virginie
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ACKNOWLEDGEMENTS
The authors would like to thank all participants involved in the three cohort studies
Open Access This article is licensed under a Creative Commons
for their devotion in clinical data collection and processing. The authors would like to
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thank Colette Reniers, Duco Buma, and the employees of the Department of adaptation, distribution and reproduction in any medium or format, as long as you give
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CENTRE-PD to R.K.), by the European Union’s EIT Health grant for MoveIT (ID: 18034), © The Author(s) 2021
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